Synthesis of zolmitriptan consists of three generally known reactions (WO97/06162): diazotation of (S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one of formula I with a nitrite in the environment of diluted hydrochloric acid, subsequent reduction of the resulting diazonium salt to the hydrochloride of (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one of formula IV and finally its condensation with 4,4-diethoxy-N,N-dimethylbutylamine of formula II, which, in an acidic environment, according to Fischer, provides an indole skeleton—in this case zolmitriptan of formula III—in a mechanism analogous to the benzidine rearrangement. The whole synthesis occurs in an aqueous environment and does not require isolation of intermediates.

As the reduction reagent in the reduction stage of the synthesis stannous chloride or an alkali sulphite, e.g. Na2SO3 (WO97/06162), is used. However, the use of stannous chloride causes problems with purification of the product and wastewater from environmentally undesirable tin salts and this is why it is not suitable in the production scale. On the other hand, Na2SO3 is relatively poorly soluble, which results either in the need of stronger dilution of the reduction mixture or in a heterogeneous reaction system (suspension). Heterogeneous reactions may then cause problems with stirring, especially in a larger scale, while dilution of the reaction mixture requires a substantial extension of the reaction time. The second stage of the reduction carried out in an acidic environment at 60° C. in this homogeneous diluted solution usually takes up to 18 hours (WO 97/06162), which, besides energy and personnel costs, also increases the undesirable heat load of the intermediate product and reduces the yield of the synthesis.
The raw product is usually recovered from the reaction mixture after its alkalization (NaOH/water) by repeated extraction with an organic solvent, generally ethyl acetate (WO 97/06162). After concentration of the extracts to a fraction of the initial volume crystalline raw zolmitriptan is obtained in the form of a solvate with ethyl acetate, which is purified through re-crystallization from the ethanol-ethyl acetate mixture and subsequently desolvated by stirring in aqueous acetone. The product—zolmitriptan base—is finally removed by filtration and washed with ethyl acetate.
However, with regard to relatively low solubility of zolmitriptan in ethyl acetate the above mentioned extraction method of isolation requires considerable volumes of the extraction agent (approx. 25-fold of the final product) and their subsequent evaporation. To say nothing of the energy and time demands of such a method, during concentration in a larger scale the product is also subject to considerable heat load which is, with regard to the increased temperature and character of the solvent, even multiplied by the mutual reactivity of the product (basic amine) with the solvent (ester) and also by hydrolysis of the product and solvent caused by the alkaline aqueous environment during the extractions.
For this reason conditions that would be able to eliminate or minimize the above mentioned negative aspects of the hitherto known methods of zolmitriptan synthesis have been sought.